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J. Biol. Chem., Vol. 279, Issue 20, 21239-21247, May 14, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/20/21239    most recent M312771200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hwang, R. Articles by Lim, S.-K. Search for Related Content PubMed PubMed Citation Articles by Hwang, R. Articles by Lim, S.-K. Social Bookmarking                      What's this?

Calcyclin, a Ca²⁺ Ion-binding Protein, Contributes to the Anabolic Effects of Simvastatin on Bone^*

Ranjoo Hwang, Eun Jin Lee, Myoung Hee Kim, Song-Zhe Li, Yong-Jun Jin, Yumie Rhee, Yoo Mee Kim, and Sung-Kil Lim¶

From the Departments of Internal Medicine and Anatomy, College of Medicine, Yonsei University, 120-752, Seoul, Korea

In vitro treatment with a pharmacological dose of simvastatin, a potent pro-drug of a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, stimulates bone formation. In our study, simvastatin stimulated differentiation of osteoblasts remarkably in a dose-dependent manner, with minimal effect on proliferation. To identify the mediators of the anabolic effects of simvastatin on osteoblasts, we tried to identify and characterize simvastatin-induced proteins by using proteomic analysis. Calcyclin was significantly up-regulated by more than 10 times, and annexin I was also up-regulated by simvastatin. However, annexin III, vimentin, and tropomyosin were down-regulated. Up-regulated calcyclin mRNA by simvastatin was validated by reverse transcription in mouse calvarial cells. In confocal microscope analysis, green fluorescence protein-calcyclin fusion protein was ubiquitously observed in the of MC3T3-E1 cells transfected with green fluorescence protein-calcyclin cDNA containing plasmid and was quickly concentrated in the nucleus 20 min after simvastatin treatment. Overexpression of calcyclin cDNA stimulated both the proliferation and expression of alkaline phosphatase mRNA significantly, without exposure to simvastatin in MC3T3-E1 cells. However, both the rate of proliferation of the osteoblasts and the expression of alkaline phosphatase mRNA were suppressed significantly 1 day after treatment with the calcyclin-specific small interference RNA, and furthermore, simvastatin did not overcome this suppression in the small interference RNA-pretreated MC3T3-E1 cells. In conclusion, calcyclin is one of the candidate proteins that plays a role in osteoblastogenesis in response to simvastatin, although the precise functions of calcyclin in osteoblast remain to be verified.

Received for publication, November 21, 2003 , and in revised form, February 5, 2004.

^* This study was supported by Grant 03-PJ10-PG6-GP01-0002 from the Korea Health 21 R & D Project, Ministry of Health & Welfare, Republic of Korea and Brain Korea 21 Project for Medical Science, Yonsei University. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 82-2-361-5432; Fax: 82-2-393-6884; E-mail: lsk{at}yumc.yonsei.ac.kr.

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